PMID- 19848404
OWN - NLM
STAT- MEDLINE
DCOM- 20091221
LR  - 20211203
IS  - 1520-4804 (Electronic)
IS  - 0022-2623 (Linking)
VI  - 52
IP  - 22
DP  - 2009 Nov 26
TI  - Discovery of potent and selective inhibitors of the mammalian target of rapamycin 
      (mTOR) kinase.
PG  - 7081-9
LID - 10.1021/jm9012642 [doi]
AB  - The mammalian target of rapamycin (mTOR) is a central regulator of cell growth, 
      metabolism, and angiogenesis and an emerging target in cancer research. High 
      throughput screening (HTS) of our compound collection led to the identification 
      of 3-(4-morpholin-4-yl-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenol 
      (5a), a modestly potent and nonselective inhibitor of mTOR and phosphoinositide 
      3-kinase (PI3K). Optimization of compound 5a, employing an mTOR homology model 
      based on an X-ray crystal structure of closely related PI3Kgamma led to the 
      discovery of 
      6-(1H-indol-5-yl)-4-morpholin-4-yl-1-[1-(pyridin-3-ylmethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine 
      (5u), a potent and selective mTOR inhibitor (mTOR IC(50) = 9 nM; PI3Kalpha IC(50) 
      = 1962 nM). Compound 5u selectively inhibited cellular biomarker of mTORC1 
      (P-S6K, P-4EBP1) and mTORC2 (P-AKT S473) over the biomarker of PI3K/PDK1 (P-AKT 
      T308) and did not inhibit PI3K-related kinases (PIKKs) in cellular assays. These 
      pyrazolopyrimidines represent an exciting new series of mTOR-selective inhibitors 
      with potential for development for cancer therapy.
FAU - Nowak, Pawel
AU  - Nowak P
AD  - Chemical Sciences, Wyeth Research, 401 N. Middletown Road, Pearl River, New York 
      10965, USA. nowakp@wyeth.com
FAU - Cole, Derek C
AU  - Cole DC
FAU - Brooijmans, Natasja
AU  - Brooijmans N
FAU - Bursavich, Matthew G
AU  - Bursavich MG
FAU - Curran, Kevin J
AU  - Curran KJ
FAU - Ellingboe, John W
AU  - Ellingboe JW
FAU - Gibbons, James J
AU  - Gibbons JJ
FAU - Hollander, Irwin
AU  - Hollander I
FAU - Hu, YongBo
AU  - Hu Y
FAU - Kaplan, Joshua
AU  - Kaplan J
FAU - Malwitz, David J
AU  - Malwitz DJ
FAU - Toral-Barza, Lourdes
AU  - Toral-Barza L
FAU - Verheijen, Jeroen C
AU  - Verheijen JC
FAU - Zask, Arie
AU  - Zask A
FAU - Zhang, Wei-Guo
AU  - Zhang WG
FAU - Yu, Ker
AU  - Yu K
LA  - eng
PT  - Journal Article
PL  - United States
TA  - J Med Chem
JT  - Journal of medicinal chemistry
JID - 9716531
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrimidines)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Binding, Competitive
MH  - Cell Line, Tumor
MH  - *Drug Discovery
MH  - Humans
MH  - Inhibitory Concentration 50
MH  - Models, Molecular
MH  - Molecular Conformation
MH  - Molecular Weight
MH  - Protein Kinase Inhibitors/chemical synthesis/chemistry/metabolism/*pharmacology
MH  - Protein Kinases/chemistry/*metabolism
MH  - Pyrimidines/chemical synthesis/chemistry/metabolism/*pharmacology
MH  - Signal Transduction/drug effects
MH  - Substrate Specificity
MH  - TOR Serine-Threonine Kinases
EDAT- 2009/10/24 06:00
MHDA- 2009/12/22 06:00
CRDT- 2009/10/24 06:00
PHST- 2009/10/24 06:00 [entrez]
PHST- 2009/10/24 06:00 [pubmed]
PHST- 2009/12/22 06:00 [medline]
AID - 10.1021/jm9012642 [doi]
PST - ppublish
SO  - J Med Chem. 2009 Nov 26;52(22):7081-9. doi: 10.1021/jm9012642.